A pathogenic particle 100 times smaller than the smallest virus, couldconceivably bring down the government of British Prime MinisterJohn Major.

This week, Major added another 100,000 head to the 1.2 millioncattle that Britain is slaughtering, to check the epizootic of "mad cowdisease." which has plagued the country for the past decade. Hislatest hike in the number of animals marked for destruction has theaim of reversing a ban on British beef exports imposed last March bythe European Union.

That embargo was in reaction to fear of possible contagion affectingthe human form of the fatal bovine transmissible spongiformencephalopathy that has decimated British herds. That humanequivalent is an equally deadly brain infection, Creutzfeldt-JakobDisease (CJD).

Major lost his majority in Parliament last week, leaving hisgovernment's survival at the mercy of votes by Northern Ireland'sUlster Unionist Party. As The New York Times pointed out on Dec.17, Northern Ireland "has the most grass-fed herds, and has sufferedthe fewest cases of the [mad cow] disease."

What both the bovine and human afflictions have in common is anenigmatic, submicroscopic pathogen called the "prion" _"proteinaceous infective agent." (See BioWorld Today, April 8,1996, p. 1.)

Besides cows, the prion infects sheep and goats with scrapie, andmink with encephalopathy. In humans, besides CJD, it causes fatalfamilial insomnia (FFI), as well as Gerstmann-Strassler-Scheinkersyndrome. (See BioWorld Today, Aug. 10, 1995, p. 1.) These are allextremely rare diseases; incidence of CJD runs one in a million cases,ten percent of them familial. FFI, with perhaps 20 to 50 knownvictims in the world, is infinitely more exotic.

When neurologist Stanley Prusiner propounded his discovery of theprion in 1981, he described it as a protein devoid of nucleic acid, andtotally unlike any virus, viroid, fungus or bacterium known. Thedoubts (not to mention hoots and scoffs) his claim raised at the timehave largely dissipated. Prions now have recognition as causingdiseases in man and beast, and these are widely researched today.

Three Prion Transmissibility Persuasions

It seems that, unique among diseases, the prion-inflicted ones areboth inherited, infectious and spontaneous versions.

Neurophysiologist Stephen DeArmond, a co-author of the Sciencepaper, told BioWorld Today: "Mutations in the prion protein genedestabilize the molecule, and causes it spontaneously to formpathogenic prion protein particles.

"The other form," DeArmond continued, "are those forms of priondisease actually acquired by infection, of which we believe thevariant CJD in Great Britain is one example. But 90 percent of thecases do not seem to be caused by a genetic predisposition, that is, amutation, nor by an infection. We call that sporadic CJD, caused by aspontaneous thermodynamic conversion from the normal to theabnormal structural form of the protein."

What remains is the large question: How can a pathogen containingno nucleic acid whatsoever transmit diseases, from cow to cow, andpresumably person to person?

Prusiner, at the University of California, San Francisco, holds that achange in 3-D protein structure rather than a gene transformation, isthe answer, and has enlisted transgenic mice to tackle thisconundrum. His paper in today's Science bears the title: "Evidencefor the conformation of the pathologic isoform of the prion proteinenciphering and propagating prion diversity."

Prusiner points to the fact that 3-D normal prion protein "has a higha-helical content and is virtually devoid of b-sheets, whereas [mutantprion protein] has a high b-sheet content." This profoundconformational change, he observes, which converts the benign to thepathogenic, "is a post-translational process that does not appear toinvolve a covalent modification of the protein."

These structural b-sheets," Prusiner has pointed out, have a possiblebearing on Alzheimer's disease. All amyloids studied to date," hetold BioWorld Today two years ago, "have a b-pleated sheetstructure." (See BioWorld Today, Feb. 10, 1994, p. 1.)

The transgenic chimeric mice his laboratory has constructed carry acombined murine and human prion gene, which renders themsusceptible to human prions. The co-authors injected extracts frompatients dead of either CJD or FFI into the animals' brains.

The mutant prion proteins that cause these disorders are chemicallysimilar, but differ in their 3-D structure. When Prusiner's co-authorscleaved CJD material with an enzyme in vitro, they got a 21-kiloDalton fragment. FFI brain extracts came up 19 kiloDaltons.

So they asked their mice whether the human prions put into theirliving brains inherit the same differing CJD and FFI fragments. Theanswer: They did. About 200 days after inoculation, FFI materialproduced the 19 kD mutant human brain fragment. Extracts fromboth familial and sporadic CJD brains yielded the 21 kD version.

"This result," the Science paper concluded, "suggest[s] a mechanismto explain strains of prions where diversity is encrypted in theconformation of [the mutant prion protein].

Viral Nucleic Acid Adherence

But neurologist Michael Harrington at California Institute ofTechnology, in Pasadena, and many others in the field, persist insuspecting that somewhere in the prion haystack lurks a virus thattransmits the diseases. As quoted in an editorial titled "Ironing outthe wrinkles in the prion strain problem," Harrington told Sciencereaders: "[Prusiner's] paper is evidence that the conformationaldifferences yield strains," but added that it doesn't prove it."

DeArmond said: "The people who support the viral, or nucleic-acidhypothesis, have no data at all. It's all based on a hope and faith thatit's gotta be a virus. Whereas the prion-only hypothesis is based on amountain of neurochemical data, which shows that the purified agentis the prion protein. If you eliminate the prion protein from an animal,by making knockout mice, you cannot propagate prions orinfectivity."

In the editorial, the paper's first author, post-doctoral fellow GeorgeTelling, observed: "There are people who will go to their gravesbelieving that these diseases are caused by viruses."

To which Prusiner added: "They can think what they want. I can'thelp them." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.